Bipolar disorder and schizophrenia are significant burdens to patients, families and society. Despite consistent evidence for high heritability (up to 80%), the etiology remains poorly understood. In 2008, several groups including ours observed that copy number variants, and in particular, large deletions each containing many genes accounted for some fraction of disease susceptibility. Several groups also identified a more general excess of rare CNVs in schizophrenia and more recently, common single nucleotide variation has been shown to contribute to a polygenic component that also accounts for a fraction of disease risk. Finally, several statistically compelling specific risk loci have also been reported. With what is proving to be a highly complex genetic landscape, existing approaches that model changes in single or small numbers of genes across development are not well suited to capture all the genetic factors interacting in an individual. Thus, the overall goal of this project is to develop human induced pluripotent stem (iPS) cell-based models of neuropsychiatric disorders that are genetically based. In the R21 Phase, pre-existing publicly available fibroblasts from bipolar disorder and schizophrenia patients along with healthy controls will be used to pilot human iPS cell model methods. Once generated, methods for the differentiation of these iPS cells into neural lineages will be employed to characterize potential between-subject and within-subject differences. Specific signaling pathways previously implicated in psychiatric disease will be characterized using a panel of neurotrophic factors and small-molecule probes of Wnt/GSK-3 signaling to develop automated microscopy- based imaging and pathway-selective reporter gene assays. Upon completion of these studies we will have established a framework for systematic development of a Mental Illness Stem Cell Library (MISCL) that will be expanded in the second R33 Phase to include samples obtained from patients from our ongoing genome-wide association studies (GWAS) of bipolar disorder and schizophrenia. The driving questions in the R33 phase will be to use iPS cells derived from clinical samples that reflect the entire genome of an individual to determine the effects on neurodevelopment of: 1) large multigenic deletions on chromosome 1q21.1, 22q11 or 15q13.1 and 2) multiple polygenes of small effect. Similarly, we will use iPS cells from individuals with bipolar disorder associated ankyrin-G (ANK3) haplotypes to determine the effect on basic ion channel physiology, molecular organization of the axon initial segment, and neuronal polarity. PUBLIC HEALTH RELEVANCE: The purpose of this Project is to use newly developed methods for reprogramming human somatic cells (e.g., fibroblasts) to create induced pluripotent stem (iPS) cells that can be used as genetically accurate models of bipolar disorder and schizophrenia. To do so we will work closely with the Harvard Stem Cell Institute (HSCI) iPS Core facility at Massachusetts General Hospital, which has extensive experience with human iPS cell technologies and have successfully derived iPS lines from adult fibroblasts. Methods for inducing the differentiation of iPS cells into neural and glial cells will be implemented as well as novel methods for phenotyping cells using imaging and plate reader assays.